Department of Bio-New Drug Development, College of Medicine, Chosun University, Gwangju, 501-759, Republic of Korea.
Arch Pharm Res. 2015 Aug;38(8):1434-42. doi: 10.1007/s12272-015-0554-2. Epub 2015 Jan 13.
Vascular endothelial growth factor-2 receptor (VEGFR-2) kinase is a promising target for the development of novel anticancer drugs. Three-dimensional quantitative structure-activity relationship (3D-QSAR) study was performed on a series of tetrahydro-3H-imidazo[4,5-c]pyridine derivatives to understand the structural basis for VEGFR-2 inhibitory activity. Several 3D-QSAR models were developed using various partial atomic charge schemes. Comparative molecular field analysis (CoMFA) and Comparative molecular similarity indices analysis (CoMSIA) methods were employed to derive these models. The CoMFA models performed better than the CoMSIA models. The reliable CoMFA model was obtained with the Gasteiger-Marsili charge scheme. The model produced statistically significant results with a cross-validated correlation coefficient (q(2)) of 0.635 and a coefficient of determination (r(2)) of 0.930. The model showed reasonable predictive power with predictive correlation coefficient ([Formula: see text]) of 0.582. Robustness of the model was further checked by leave-five-out cross-validation, bootstrapping and progressive scrambling analysis. The model was found to be statistically robust and expected to assist in the design of novel compounds with enhanced VEGFR-2 inhibitory activity.
血管内皮生长因子-2 受体（VEGFR-2）激酶是开发新型抗癌药物的有前途的靶标。对一系列四氢-3H-咪唑并[4,5-c]吡啶衍生物进行了三维定量构效关系（3D-QSAR）研究，以了解 VEGFR-2 抑制活性的结构基础。使用各种部分原子电荷方案开发了几个 3D-QSAR 模型。采用比较分子场分析（CoMFA）和比较分子相似性指数分析（CoMSIA）方法得出这些模型。CoMFA 模型的性能优于 CoMSIA 模型。使用 Gasteiger-Marsili 电荷方案获得了可靠的 CoMFA 模型。该模型产生了具有统计学意义的结果，交叉验证相关系数（q(2)）为 0.635，决定系数（r(2)）为 0.930。该模型具有合理的预测能力，预测相关系数（[Formula: see text]）为 0.582。通过留一法交叉验证、引导和逐步随机分析进一步检查了模型的稳健性。该模型被发现具有统计学上的稳健性，并有望辅助设计具有增强的 VEGFR-2 抑制活性的新型化合物。
